Exudative cutaneous ulcers (CU) in the tropics are usually attributed to attributed to Treponema pallidum subsp. pertenue (TP), or yaws, which primarily affects children 6-10 years old in poor rural communities and leads to chronic disfigurement and disability. The World Health Organization (WHO) has led several campaigns to eliminate yaws, but the global prevalence of CU is substantial, with ~100 million children at risk for infection. Surprisingly, data from the current yaws elimination campaign shows that the etiology of CU is multifactorial. On Lihir island in Papua New Guinea, Haemophilus ducreyi (HD) and / or TP are detected in ~70% of CU cases, but up to ~30% have no discernable etiology; this group is defined as having idiopathic ulcers (IU). Mass drug administration (MDA) of azithromycin and subsequent case finding and treatment reduced the prevalence of CU from ~10% to 1-2% after 42 mo. of follow-up, at which time the trial was halted due to futility. Since a 1-2% prevalence of CU is unacceptable, WHO has proposed an Integrated Disease Management Strategy (IDM), which requires the development of common clinical and laboratory diagnostic platforms for CU so that individuals can be treated with targeted and effective therapeutic agents. Thus, there is a pressing need to determine the microbial etiology of IU, so that the IDM strategy can be developed. We assembled a team of scientists who are highly skilled in the studies of CU and of the skin microbiome. Our team will examine several hypotheses about the etiology of CU by determining the microbiomes of paired skin swabs that were prospectively obtained 36, 42, and 48 months after MDA on Lihir island in children with CU (N = 274) and asymptomatic, gender and age- matched household or community controls without CU. We hypothesize that some cases of IU are caused by previously unidentified pathogens that may be part of the normal skin microbiota or are caused by high loads of microorganisms not known to be ulcer pathogens. Our specific aims are to 1) identify IU associated microorganisms using a combination of deep 16S rRNA gene sequencing and metagenomic sequencing; 2) demonstrate that IU associated taxa are present in higher loads in IU vs. HD, TP or HD/TP ulcers by quantitative PCR. Our preliminary data show that 16S rRNA gene and metagenomic sequencing are feasible on the collected samples and suggest that the CU microbiome is less diverse and has a different community structure than that of its corresponding asymptomatic controls. The importance of this study is that it will be the first to characterize the microbiome of CU in children using skin swabs prospectively collected after implementation of the yaws elimination program. Identification of the agents of IU and determination of whether they are part of the normal flora is critical for the development of diagnostic tests that will lead to selective therapies as part of the IDM strategy.